Obesity is a prevalent and serious metabolic disease, and is the most significant risk factor for type 2 diabetes and cardiovascular and cerebrovascular diseases. Obesity develops when energy intake continuously exceeds energy expenditure (thermogenesis), which includes basal metabolism, adaptive thermognesis (cold- and diet- induced thermogenesis, DIT) and physical activity. While abnormalities in DIT contribute to the pathogenesis of some forms of obesity, low levels of physical activity are a major predictor of fat mass accumulation during overfeeding in humans. Growing evidence indicates that the central melanocortin system (CMS) plays a critical role in the regulation of energy balance in both rodents and humans. Haploinsufficiency of the melanocortin receptor 4 (MC4R) results in severe human obesity in 5.8 % of pediatric cases. In the rodent, MC4R deficiency causes obesity, in part, through reducing energy expenditure since pair-feeding animals to the level of intake observed in wild type animals still produces obesity, and MC4R deficiency mice display an impaired DIT and physical activity responding to a high fat diet (HF). More research is needed to confirm the similar roles of the MC4R in humans. We have recently demonstrated that MC4R signaling is critical in both acute cold and HF- induced brown adipose tissue (BAT) thermogenesis. We also characterized the neuroanatomical pathways involved, including MC4R neurons in multiple nuclei including the paraventricular nucleus of hypothalamus (PVH) and the brainstem raphe pallidus nucleus (RPa). While BAT thermogenesis is an excellent model system for understanding the central control of thermogenesis in rodents and data are developing that BAT also exists in young and adult humans besides newborns thus it can be potentially pharmaceutically targeted to combat obesity, skeletal muscle (SM) appears to be the principle thermogenic site in man. While our long- term goal of this research is to better understand how the CMS regulates thermogenesis, the goal of this proposal will thus be to expand our characterization of the control of thermogenesis to include the control of muscle thermogenesis and physical activity by the CMS. The specific aims of this study include I). Characterize the neuronal circuits of the CMS in the regulation of thermogenesis, including the sympatho- motor circuits of CMS regulating SM activities; II). Determine the functional activities of putative CMS pathways regulating thermogenesis, including the intrinsic and presumptive underlying afferent and downstream signal mechanisms. III). Clarify the cellular electrophysiological mechanisms underlying the melanocortin circuits regulating thermogenesis. This study should provide new insight into the mechanisms of the CMS in the regulation of thermogenesis, thus potentially contributing to the design of new pharmaceutical approaches to the management of obesity and associated diseases. PUBLIC HEALTH RELEVANCE: Obesity, resulting from an imbalance between food intake and energy expenditure, is a prevalent and serious metabolic disease, and is the most significant risk factor for type 2 diabetes and cardiovascular and cerebrovascular diseases. The major goal of this work is trying to better understand how the central melanocortin system, a key player of the brain in the regulation of energy balance, regulates thermogenesis, which includes basal metabolism, adaptive thermogenesis and physical activity. This study should provide new insight into the mechanisms underlying the central melanocortin system regulating thermogenesis, thus potentially contributing to the design of new melanocortin-based pharmaceutical approaches to the management of obesity and associated diseases. [unreadable] [unreadable] [unreadable]